Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

Abstract

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P₁₋₅. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

Keywords: Drug discovery; FTY720; Fingolimod; G protein-coupled receptor; S1P agonist; Sphingosine 1-phosphate.

Fig. 1.

Action mechanism of fingolimod and other S1P receptor modulators. Fingolimod is transformed to fingolimod-phosphate in vivo by sphingosine kinases. Fingolimod-phosphate can activate S1P₁, S1P₃, S1P₄, and S1P₅, and the fingolimod activation of S1P₁ in lymphocytes leads to GRK2-mediated phosphorylation of C-terminal tail of S1P₁, which recruits β-arrestin and induces S1P₁ internalization. This internalization exposes S1P₁ to proteosomal degradation, which prevents the recycling of S1P₁ and results in the loss of S1P₁ from the plasma membrane. This absence of S1P₁ blocks lymphocyte egression from secondary lymphoid organs and reduces T and B cell counts in the blood. Lymphopenia is presumed to be the main mechanism whereby fingolimod causes immune suppression in autoimmune diseases like relapsing multiple sclerosis.